Sause for the Goose, Sauce for the Gander: Low Tidal Volume Ventilation in the Operating Theatre

PIBW is based on height, not weight.

Following my usual procedure, I read the title and abstract of the methods of this article on Intraoperative Low Tidal Volume Ventilation in this week's NEJM, and I made a wager with myself on what the outcome would be.  Because there are both biological plausibility and biological precedent for low tidal volume, and because it is one of the few interventions in critical care in which I have supreme confidence (yes, you can conclude that I'm biased), my prior probability for this intervention is high and I wagered that the study would be positive.  If you have not already done so, read the methods in the abstract and make your own wager before you read on.

This trial is solid but not bombproof.  Outcomes assessors were blinded and so were post-operative care providers, but anesthesiologists administering tidal volumes were not.  Outcomes themselves, while mostly based on consensus definitions (sometimes a consensus of collective ignorance), are susceptible to ascertainment and misclassification biases.  The outcome was a composite, something that I like, as will be elaborated in a now published letter in AJRCCM.  A composite outcome allows an additive effect between component outcomes and effectively increases study power.  This is essential in a study such as this, where only 400 patients were enrolled and the study had "only" 80% power to detect a reduction in the primary outcome from 20% to 10%.  As we have shown, detecting a difference of this magnitude in mortality is a difficult task indeed, and most critical care studies seeking such a difference are effectively underpowered.  How many effective (in some aspect other than mortality) therapies have been dismissed because of this systemic underpowering in critical care research is anybody's guess.

A Centrum a Day Keeps the Cancer at Bay?

Alerted as usual by the lay press to the provocative results of a non-provocative study, I read with interest the article in the October 17th JAMA by Gaziano and colleagues: Multivitamins in the Prevention of Cancer in Men. From the lay press descriptions (see: NYT summary and a less sanguine NYT article published a few days later,) I knew only that it was a positive (statistically significant) study, that the reduction in cancer observed was 8%, that a multivitamin (Centrum Silver) was used, and the study population included 14,000 male physicians.

Needless to say, in spite of a dormant hope something so simple could prevent cancer, I was skeptical. Despite decades, perhaps eons of enthusiasm for the use of vitamins, minerals, and herbal remedies, there is, to my knowledge (please, dear reader, direct me to the data if this is an omission) no credible evidence of a durable health benefit from taking such supplements in the absence of deficiency. But supplements have a lure that can beguile even the geniuses among us (see: Linus Pauling). So before I read the abstract and methods to check for the level of statistical significance, the primary endpoint, the number of endpoints, and sources of bias, I asked myself: "What is the probability that taking a simple commercially available multivitamin can prevent cancer?" and "what kind of P-value or level of statistical significance would I require to believe the result?" Indeed, if you have not yet seen the study, you can ask yourself those same questions now.

Fever, external cooling, biological precedent, and the epistemology of medical evidence

It is rare occasion that one article allows me to review so many aspects of the epistemology of medical evidence, but alas Schortgen et al afforded me that opportunity in the May 15th issue of AJRCCM.

The issues raised by this article are so numerous that I shall make subsections for each one. The authors of this RCT sought to determine the effect of external cooling of febrile septic patients on vasopressor requirements and mortality. Their conclusion was that "fever control using external cooling was safe and decreased vasopressor requirements and early mortality in septic shock." Let's explore the article and the issues it raises and see if this conclusion seems justified and how this study fits into current ICU practice.

PRIOR PROBABILITY, BIOLOGICAL PLAUSIBILITY, and BIOLOGICAL PRECEDENTS

These are related but distinct issues that are best considered both before a study is planned, and before its report is read. A clinical trial is in essence a diagnostic test of a hypothesis, and like a diagnostic test, its influence on what we already know depends not only on the characteristics of the test (sensitivity and specificity in a diagnostic test; alpha and power in the case of a clinical trial) but also on the strength of our prior beliefs. To quote Sagan [again], "extraordinary claims require extraordinary evidence." I like analogies of extremes: no trial result is sufficient to convince the skeptical observer that orange juice reduces mortality in sepsis by 30%; and no evidence, however cogently presented, is sufficient to convince him that the sun will not rise tomorrow. So when we read the title of this or any other study, we should pause to ask: What is my prior belief that external cooling will reduce mortality in septic shock? That it will reduce vasopressor requirements?